tbuckley/cabot-search huggingface dataset:
A phase 1/2 of carfilzomib and melphalan conditioning for autologous stem cell transplantation for multiple myeloma (<scp>CARAMEL</scp>)
Authors: Alissa Visram, Suzanne R. Hayman, Angela Dispenzieri, Prashant Kapoor, Martha Q. Lacy, Morie A. Gertz, Francis K. Buadi, David Dingli, Rahma Warsame, Taxiarchis Kourelis, Joselle Cook, Moritz Binder, Wilson Gonsalves, Eli Muchtar, Nelson Leung, Vivek Roy, S. Vincent Rajkumar, Shaji Kumar
Journal: American Journal of Hematology (2023)

Abstract In this phase 1/2 study, carfilzomib was added to high‐dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days −6, −5, −2, and −1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m 2 on days −4 and −3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m 2 (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4–88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3–4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.
Independent SARS-CoV-2 staff testing protected academic and health-care institutions in northwest London
Authors: Chris Bailey, Theo Sanderson, Hermaleigh Townsley, Jacki Goldman, James R M Black, George Young, Robert Goldstone, Ashley S Fowler, Sophia Ward, Deborah J Jackson, Laura Cubitt, Vicky Dearing, Olga O'Neil, Marg Crawford, Daniel Snell, Makis Finadis, Amelia Edwards, Jimena Perez-Lloret, Joshua Gahir, Edward J Carr, Andy Riddell, Jim Aitken, Karen Ambrose, Chelsea Sawyer, Nicola O'Reilly, Simon Caidan, Mary Y Wu, Philip A Walker, Steve Hindmarsh, Michael Howell, Andrew Jordan, James Fleming, Catherine Houlihan, Eleni Nastouli, Rachel Moores, Desmond Hsu, Padmasayee Papineni, Tumena Corrah, Richard Gilson, James MacRae, Michael Hubank, Nicholas Van As, Samra Turajlic, Rupert Beale, Marcel Levi, Sam Barrell, Bryan Williams, Steve Gamblin, Jerome Nicod, Sonia Gandhi, David L V Bauer, Emma C Wall, Charles Swanton
Journal: The Lancet (2023)
A three-level model for therapeutic drug monitoring of antimicrobials at the site of infection
Authors: Noé Brasier, H Ceren Ates, Juliane R Sempionatto, Menino O Cotta, Andreas F Widmer, Jens Eckstein, Jörg Goldhahn, Jason A Roberts, Wei Gao, Can Dincer
Journal: The Lancet Infectious Diseases (2023)
Tenofovir versus entecavir on the prognosis of hepatitis B-related hepatocellular carcinoma after surgical resection: a randomised controlled trial
Authors: He Linye, Xia Zijing, Zhang Xiaoyun, Li Zhihui, Wen Tianfu, Li Chuan
Journal: International Journal of Surgery (2023)

Background: Nucleot(s)ide analog treatment (entecavir (ETV) and tenofovir (TDF)) is reported to be associated with decreased tumor recurrence and death in HBV-related hepatocellular carcinoma (HCC) patients, yet further work is needed to evaluate the different efficacies of these two agents on the prognosis of early-stage HBV-related HCC patients after curative liver resection. Material and methods: From July 2017 to January 2019, 148 patients with HBV-related HCC who underwent curative liver resection were randomized to receive TDF (n=74) or ETV (n=74) therapy. The primary end point was tumor recurrence in the intention-to-treat (ITT) population. Overall survival (OS) and tumor recurrence of patients were compared by multivariable-adjusted Cox regression and competing risk analyses. Results: During the follow-up with continued antiviral therapy, 37 (25.0%) patients developed tumor recurrence, and 16 (10.8%) patients died (N=15) or received liver transplantation (N=1). In the ITT cohort, the recurrence-free survival for the TDF group was significantly better than that for the ETV group ( P =0.026). In the multivariate analysis, the relative risks of recurrence and death/liver transplantation for ETV therapy were 3.056 (95% confidence interval (CI): 1.015-9.196; P =0.047) and 2.566 (95% CI: 1.264-5.228; P =0.009), respectively. Subgroup analysis of the PP population indicated a better OS and RFS of patients receiving TDF therapy ( P =0.048; HR =0.362; 95% CI: 0.132-0.993 and P =0.014; HR =0.458; 95% CI: 0.245-0.856). Additionally, TDF therapy was an independent protective factor against late tumor recurrence ( P =0.046; hazard ratio (HR)=0.432; 95% CI: 0.189-0.985) but not against early tumor recurrence ( P =0.109; HR =1.964; 95% CI: 0.858-4.494). Conclusion: HBV-related HCC patients treated with consistent TDF therapy had a significantly lower risk of tumor recurrence than those treated with ETV after curative treatment.
Efficacy of vaginal natural orifice transluminal endoscopic sentinel lymph node biopsy for endometrial cancer: a prospective multicenter cohort study
Authors: Li Deng, Yi Liu, Yuanyan Yao, Yuan Deng, Shuai Tang, Li Sun, Yanzhou Wang
Journal: International Journal of Surgery (2023)

Natural orifice transluminal endoscopic surgery (NOTES) is performed increasingly often despite the lack of high-quality evidence confirming its safety, especially for malignant diseases. The aim of this prospective study is to verify that vaginal NOTES (vNOTES) can be performed safely and effectively in early endometrial cancer staging surgery.This prospective study was conducted in two tertiary hospitals in southern China from January 2021 to May 2022. A total of 120 patients with stage I endometrial cancer were included. vNOTES or multiport laparoscopic staging surgery was selected according to each patient's wishes. The primary outcome was the sentinel lymph node detection rate, analyzed by a noninferiority test. The secondary outcomes were perioperative outcomes.Among the 120 patients enrolled, 57 underwent vNOTES, and 63 underwent multiport laparoscopy. The patient-specific detection rates of sentinel lymph nodes were 94.73 and 96.82% in the vNOTES and laparoscopy groups, respectively. Additionally, the bilateral detection rates were 82.46 and 84.13%, and the side-specific detection rates were 88.60 and 90.48% in these two groups, respectively. All three detection rates in the vNOTES group were noninferior to those of laparoscopy group at a noninferiority cutoff of -15%. The median operation times of the vNOTES and laparoscopy groups were 132.35 and 138.73 min ( P =0.362), and the median estimated blood loss were 75 and 50 ml ( P =0.096), respectively. No intraoperative complications occurred in either group. The pain scores on the Numerical Rating Scale at both 12 h and 24 h after operation were significantly lower in the vNOTES group ( P <0.001) and the median postoperative hospital stay was significantly shorter in the vNOTES group ( P =0.001).This study illustrates the potential applicability of vNOTES in gynecological malignancy surgery by demonstrating its safety and effectiveness in endometrial cancer staging. However, its long-term survival outcomes require further exploration.
Psychological symptoms do not discriminate between reflux phenotypes along the organic-functional refractory GERD spectrum
Authors: Annelies Geeraerts, Livia Guadagnoli, Ans Pauwels, Hannelore Geysen, Thomas Neyens, Lukas Van Oudenhove, Tim Vanuytsel, Jan Tack
Journal: Gut (2023)

Historically, psychological processes are associated with disorders at the functional end of the gastro-oesophageal reflux disease (GERD) spectrum. However, recent research suggests that psychological symptoms are relevant across the entire GERD spectrum. We aim to investigate whether psychological symptoms are associated with reflux phenotype (True GERD, Borderline GERD, reflux hypersensitivity, functional heartburn) along the GERD spectrum in a cohort of refractory reflux patients.Consecutive adult patients with refractory reflux symptoms underwent standard 24-hour pH-impedance monitoring and completed questionnaires assessing demographic, clinical and psychological information. Bayesian one-way analysis of variance assessed whether psychological variables differed across reflux phenotypes. Next, we applied multinomial and ordinal logistic regressions with clinical, demographic and psychological variables set as independent variables and reflux phenotype as the outcome variable. The complementary machine-learning approach entered all demographic, clinical and psychological variables into models, with reflux phenotype set nominally and ordinally. Cross-validated model performance was used to select the best model.393 participants (mean (SD) age=48.5 (14.1); 60% female) were included. The Bayesian analyses found no difference in psychological variables across reflux phenotypes. Similarly, age, gender and proton pump inhibitor use were the only significant variables in the multinomial logistic regression and body mass index was significant in both regressions. Machine-learning analyses revealed poorly performing models with high misclassification rates (67-68%) in both models.Psychological symptoms do not differ between nor predict reflux phenotype membership in refractory reflux patients. Findings suggest that psychological symptoms are relevant across the spectrum of GERD, rather than specific to functional oesophageal disorders.
c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation
Authors: Yuquan Xiong, Meriem Taleb, Kyohei Misawa, Zhaohua Hou, Srijita Banerjee, Alfredo Amador-Molina, David R Jones, Navin K Chintala, Prasad S Adusumilli
Journal: Nature Cancer (2023)
Extrastriatal Accumulation of 18F-FP-CIT at Cerebral Infarction in a Patient With Suspected Parkinson Disease
Authors: Jihye Yoo, In Kook Chun
Journal: Clinical Nuclear Medicine (2023)

Abstract 18 F-FP-CIT PET/CT is a useful diagnostic tool for differentiating between idiopathic Parkinson disease and atypical Parkinson syndrome by visualizing the striatum, where the nerve endings of nigrostriatal dopaminergic neurons are located. We present an unusual accumulation of 18 F-FP-CIT in the infarct and peri-infarct brain area of an 83-year-old man who was referred for the management of suspected cerebral infarction due to sudden dysarthria and delirium.
Towards net zero: asthma care
Authors: Laura-Jane E Smith, Ruhi Bhugra, Reem Y Kelani, James Smith
Journal: BMJ (2023)

Wilkinson AJK, Menzies-Gow A, Sawyer M, et al. S26 An assessment of short-acting β2-agonist (SABA) use and subsequent greenhouse gas (GHG) emissions in five European countries and the consequence of their potential overuse for asthma in the UK. Thorax2021;76(Suppl 1):A19.
A framework for assessing selection and misclassification bias in mendelian randomisation studies: an illustrative example between body mass index and covid-19
Authors: Gemma L Clayton, Ana Gonçalves, None Soares, Neil Goulding, Maria Carolina Borges, Michael V Holmes, George Davey, None Smith, Kate Tilling, Deborah A Lawlor, Alice R Carter
Journal: BMJ (2023)

Mendelian randomisation (MR) studies, which investigate causal effects of exposures on disease, might be biased by sample selection and misclassification if phenotypes are not measured universally with the same definition in all study populations or participants. For example, in MR analyses of effects of exposures on covid-19, studies might include individuals with specific characteristics (eg, high socioeconomic position) meaning they are more likely to be tested for SARS-CoV-2 infection or respond to study questionnaires collecting data on infection and disease (selection bias). Alternatively, studies might assume those who were not tested have not been infected by SARS-CoV-2 or had covid-19 and are included as control participants (misclassification bias). In this article, a set of analyses to investigate the presence of selection or misclassification bias in MR studies is proposed and the implications of these on results is considered. The effect of body mass index on covid-19 susceptibility and severity is used as an illustrative example.
The effect of background noise and its removal on the analysis of single-cell expression data
Authors: Philipp Janssen, Zane Kliesmete, Beate Vieth, Xian Adiconis, Sean Simmons, Jamie Marshall, Cristin McCabe, Holger Heyn, Joshua Z Levin, Wolfgang Enard, Ines Hellmann
Journal: Genome biology (2023)

In droplet-based single-cell and single-nucleus RNA-seq experiments, not all reads associated with one cell barcode originate from the encapsulated cell. Such background noise is attributed to spillage from cell-free ambient RNA or barcode swapping events.
Cross-ancestry genome-wide association meta-analyses of hippocampal and subfield volumes
Authors: Nana Liu, Longjiang Zhang, Tian Tian, Jingliang Cheng, Bing Zhang, Shijun Qiu, Zuojun Geng, Guangbin Cui, Quan Zhang, Weihua Liao, Yongqiang Yu, Hui Zhang, Bo Gao, Xiaojun Xu, Tong Han, Zhenwei Yao, Wen Qin, Feng Liu, Meng Liang, Qiang Xu, Jilian Fu, Jiayuan Xu, Wenzhen Zhu, Peng Zhang, Wei Li, Dapeng Shi, Caihong Wang, Su Lui, Zhihan Yan, Feng Chen, Jiance Li, Jing Zhang, Dawei Wang, Wen Shen, Yanwei Miao, Junfang Xian, Jia-Hong Gao, Xiaochu Zhang, Mulin Jun Li, Kai Xu, Xi-Nian Zuo, Meiyun Wang, Zhaoxiang Ye, Chunshui Yu, Quan Zhang, Junping Wang, Xue Zhang, Xinjun Suo, Congcong Yuan, Yuan Ji, Hui Xue, Tianying Gao, Junpeng Liu, Yanjun Li, Xi Guo, Lixue Xu, Jiajia Zhu, Huaigui Liu, Fangshi Zhao, Jie Sun, Yongjie Xu, Huanhuan Cai, Jie Tang, Yaodan Zhang, Yongqin Xiong, Xianting Sun, Nannan Pan, Xue Zhang, Jiayang Yang, Ya Wen, None Dan Zhu, Bingjie Wu, Wenshuang Zhu, Qingqing Diao, Yujuan Cao, Bingbing Yang, Lining Guo, Yingying Xie, Jiahui Lin, Zhimin Li, Yan Zhang, Kaizhong Xue, Zirui Wang, Junlin Shen, Xuejun Zhang, Hao Ding, Qian Su, Shijie Zhang, Lun Ma, Yan Bai, Min Guan, Wei Wei, Peifang Miao, Fuhong Duan, Yafei Guo, Weijian Wang, Lijuan Zheng, Li Lin, Yunfei Wang, Han Zhang, Xinyuan Zhang, Zhao Qing, Sichu Wu, Junxia Wang, Yi Sun, Yang He, Zhe Zhang, Yin-Shan Wang, Quan Zhou, Yi Liang, Yujie Liu, Hui Zeng, Jingxian Chen, Haitao Ge, Peng Xu, Cailuan Lu, Chen Wu, Xiaoying Yang, Yuzhao Wang, Yankai Wu, Xuran Feng, Ling Li, Duo Gao, Rujing Zha, Ying Li, Lizhuang Yang, Ying Chen, Ling Zuo, Jianqiao Ge, Guoyuan Yang, Wen Wang, Linfeng Yan, Yang Yang, Jin Zhang, Qian Wang, Xiaoxia Qu, Ying Wang, Fei Yuan, Li Hu, Jizhen Li, Weiwei Wang, Yujing Zhou, Miaomiao Long, Lihua Liu, Xiaohu Li, Xiaoshu Li, Yunjun Yang, Nengzhi Xia, Shuai Yang, Youming Zhang, Guangyao Liu, Laiyang Ma, Xiaochun Wang, Ying Lei, Gang Zhang, Kang Yuan, Jingjing Xu, Xiaojun Guan, Yuankai Lin, Huijuan Chen, Yuchuan Fu, Yi Lu, Jun Guo, Hao Lu, Yue Wu
Journal: Nature Genetics (2023)
Bio-enhanced fraction from Clitoria ternatea root extract ameliorates cognitive functions and in vivo hippocampal neuroplasticity in chronic cerebral hypoperfusion rat model
Authors: Mohamad Anuar Ahad, Nelson Jeng-Yeou Chear, Lim Gin Keat, Ahmad Tarmizi Che Has, Vikneswaran Murugaiyah, Zurina Hassan
Journal: Ageing Research Reviews (2023)
Successful large gene augmentation of USH2A with non-viral episomal vectors
Authors: Maria Toms, Lyes Toualbi, Patrick V. Almeida, Richard Harbottle, Mariya Moosajee
Journal: Molecular Therapy (2023)

USH2A mutations are a common cause of autosomal recessive retinitis pigmentosa (RP) and Usher syndrome, for which there are currently no approved treatments. Gene augmentation is a valuable therapeutic strategy for treating many inherited retinal diseases, however conventional adeno-associated virus (AAV) gene therapy cannot accommodate cDNAs exceeding 4.7kb, such as the 15.6kb-long USH2A coding sequence. In the present study, we adopted an alternative strategy to successfully generate scaffold/matrix attachment region (S/MAR) DNA plasmid vectors containing the full-length human USH2A coding sequence, a GFP reporter gene and a ubiquitous promoter (CMV or CAG), reaching a size of approximately 23kb. We assessed the vectors in transfected HEK-293 cells and USH2A patient-derived dermal fibroblasts, in addition to ush2au507 zebrafish microinjected with the vector at the one-cell stage. pS/MAR-USH2A vectors drove persistent transgene expression in patient fibroblasts with restoration of usherin. Twelve months of GFP expression was detected in the photoreceptor cells, with rescue of Usher 2 complex localisation in the photoreceptors of ush2au507 zebrafish retina injected with pS/MAR-USH2A. To our knowledge, this is the first reported vector which can be used to express full-length usherin with functional rescue. S/MAR DNA vectors have shown promise as a novel non-viral retinal gene therapy, warranting further translational development.
Single-cell transcriptome profiling of sepsis identifies HLA-DRlowS100Ahigh monocytes with immunosuppressive function
Authors: Ren-Qi Yao, Peng-Yue Zhao, Zhi-Xuan Li, Yu-Yang Liu, Li-Yu Zheng, Yu Duan, Lu Wang, Rong-Li Yang, Hong-Jun Kang, Ji-Wei Hao, Jing-Yan Li, Ning Dong, Yao Wu, Xiao-Hui Du, Feng Zhu, Chao Ren, Guo-Sheng Wu, Zhao-Fan Xia, Yong-Ming Yao
Journal: Military Medical Research (2023)

Abstract Background Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. Methods We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9 + monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9 −/− mice were co-cultured with naïve CD4 + T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. Results ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DR low S100A high monocytes in human sepsis. Moreover, we found that S100A9 + monocytes exhibited profound immunosuppressive function on CD4 + T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. Conclusions This study identifies HLA-DR low S100A high monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.
Overcoming proteasome inhibitor resistance in the immunotherapy era
Authors: Bonell Patiño-Escobar, Alexis Talbot, Arun P. Wiita
Journal: Trends in Pharmacological Sciences (2023)

Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma. However, PIs are not curative, and overcoming PI resistance to extend patient survival remains a major unmet need. Recent strategies to overcome PI resistance, including inhibiting alternative protein homeostasis pathways and targeting the mitochondrion as a nexus of metabolic adaptation to PIs, are gaining momentum. However, these focused approaches may be surpassed or even obviated by quickly emerging immunotherapy strategies that do not selectively target PI resistance mechanisms but are highly efficacious in PI-resistant disease, nonetheless. Informed by insights from these promising areas of research moving in parallel, we propose that pharmacological strategies to enforce immunotherapeutic vulnerabilities in resistant disease may provide a unified outlook to overcome PI resistance in a 'new era' of myeloma treatment.
Protein/Polysaccharide Composite toward Multi‐in‐One Toxin Removal in Blood with Self‐Anticoagulation and Biocompatibility
Authors: Mengjie Li, Mengmeng Chen, Facui Yang, Rongrong Qin, Qingmin Yang, Hao Ren, Han Liu, Peng Yang
Journal: Advanced Healthcare Materials (2023)

Biocompatible adsorbents play an essential role in hemoperfusion. Nevertheless, there are no hemoperfusion adsorbents that can simultaneously remove small and medium toxins, including bilirubin, urea, phosphor, heavy metals, and antibiotics. This bottleneck significantly impedes the miniaturization and portability of hemoperfusion materials and devices. Herein, a biocompatible protein-polysaccharide complex is reported that exhibits "multi-in-one" removal efficacy for liver and kidney metabolism wastes, toxic metal ions, and antibiotics. Through electrostatic interactions and polysaccharide-mediated coacervation, adsorbents can be prepared by simply mixing lysozyme (LZ) and sodium alginate (SA) together in seconds. The LZ/SA absorbent presented high adsorption capacities for bilirubin, urea, and Hg2+ of up to 468, 331, and 497 mg g-1 , respectively, and the excellent anti-protein adsorption endowed LZ/SA with a record-high adsorption capacity for bilirubin in the interference of serum albumin to simulate the physiological environment. The LZ/SA adsorbent also has effective adsorption capacity for heavy metals (Pb2+ , Cu2+ , Cr3+ , and Cd2+ ) and multiple antibiotics (terramycin, tetracycline, enrofloxacin, norfloxacin, roxithromycin, erythromycin, sulfapyrimidine, and sulfamethoxazole). Various adsorption functional groups exposed on the adsorbent surface significantly contribute to the excellent adsorption capacity. This fully bio-derived protein/alginate-based hemoperfusion adsorbent has great application prospects in the treatment of blood-related diseases.